Oily cold water fish, such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids. Omega-3 fatty acids have previously been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been shown to improve in overweight hypertensive subjects through treatment with omega-3 fatty acids. Omega-3 fatty acids (EPA/DHA) have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as part of the dietary supplement portion of therapy used to treat dyslipidemia. Last, but not least, omega-3 fatty acids have been known to have a number of anti-inflammatory properties. For instance, a higher intake of omega-3 fatty acids lower levels of circulating TNF-α and IL-6, two of the cytokines that are markedly increased during inflammation processes (Chapkin et al, Prostaglandins, Leukot Essent Fatty Acids 2009, 81, p. 187-191; Duda et al, Cardiovasc Res 2009, 84, p. 33-41). In addition, a higher intake of omega-3 fatty acids has been shown to increase levels of the well-characterized anti-inflammatory cytokine IL-10 (Bradley et al, Obesity (Silver Spring) 2008, 16, p. 938-944). More recently, administration of omega-3 fatty acids could protect against pathologic retinal angiogenesis in a mouse model of oxygen-induced retinopathy (K. M. Connor et al, Nat. Med. 2007, 13, p. 868-873; P. Sapieha et al Science Translational Medicine 2011, 3, issue 69, p. 1-12). Because of this anti-angiogenic property, omega-3 fatty acids could potentially be used as an anti-VEGF (vascular endothelial growth factor) therapy for the treatment of proliferative retinopathy or systemic diseases with perturbed vascular growth such as cancer.
Both DHA and EPA are characterized as long chain fatty acids (aliphatic portion between 12-22 carbons). Medium chain fatty acids are characterized as those having the aliphatic portion between 6-12 carbons. Lipoic acid is a medium chain fatty acid found naturally in the body. It plays many important roles such as free radical scavenger, chelator to heavy metals and signal transduction mediator in various inflammatory and metabolic pathways, including the NF-κB pathway (Shay, K. P. et al. Biochim. Biophys. Acta 2009, 1790, 1149-1160). Lipoic acid has been found to be useful in a number of chronic diseases that are associated with oxidative stress (for a review see Smith, A. R. et al Curr. Med. Chem. 2004, 11, p. 1135-46). Lipoic acid has now been evaluated in the clinic for the treatment of diabetes (Morcos, M. et al Diabetes Res. Clin. Pract. 2001, 52, p. 175-183) and diabetic neuropathy (Mijnhout, G. S. et al Neth. J. Med. 2010, 110, p. 158-162). Lipoic acid has also been found to be potentially useful in treating cardiovascular diseases (Ghibu, S. et al, J. Cardiovasc. Pharmacol. 2009, 54, p. 391-8), Alzheimer's disease (Maczurek, A. et al, Adv. Drug Deliv. Rev. 2008, 60, p. 1463-70) and multiple sclerosis (Yadav, V. Multiple Sclerosis 2005, 11, p. 159-65; Salinthone, S. et al, Endocr. Metab. Immune Disord. Drug Targets 2008, 8, p. 132-42).
COX inhibitors are non-steroidal anti-inflammatory agents which act as inhibitors of cyclooxygenase (COX). COX converts arachidonic acid to prostaglandin H2, which is subsequently converted to the prostaglandins, potent mediators of inflammation. COX inhibitors inhibit multiple isoforms of the cyclooxygenase enzyme. Inhibition of COX-2 imparts the anti-inflammatory and analgesic properties of COX inhibitors while the inhibition of COX-1 is responsible for the unwanted effects on platelet aggregation and the gastrointestinal tract (Rao, P.; Knaus, E. E. J. Pharm. Sci. 2008, 11 (2), 81S-110S). More recently, there have been reports that showed the potential benefits of administering non-steroidal anti-inflammatory drugs, along with an antioxidant, can protect against the development of Alzheimer's disease (P. Sozio et al, Arch. Pharm. Chem. Life Sci. 2010, 343, p. 133-142; M. A. Lovell et al J. Alzheimers' Disease 2003, 5, p. 229-239). In particular, ibuprofen and indomethacin are two of the COX inhibitors that have been shown to have a positive impact on the production of amyloid β peptide in cell cultures (S. Weggen et al Nature 2001, 414, p. 212-216; S. Vlad et al, Neurology 2008, 70, p. 1672-1677; A. McKee Brain Res. 2008; 1207, p. 225-236). Fatty acid COX inhibitor derivatives are inactive against the COX enzyme until they enter the cell and are hydrolyzed into the individual components to produce free COX inhibitor and free fatty acid. Thus, the side effects of COX inhibitors, including stomach ulcer and gastrointestinal distress, are minimized.
The ability to provide the effects of COX inhibitors and fatty acids in a synergistic way would provide benefits in treating a variety of metabolic, autoimmune and inflammatory disorders.